PROJECT 2 - Gene x stress interactions' impacts on pathways to type 2 diabetes PROJECT SUMMARY There is a strong association between obesity, in particular central obesity, and risk to develop type 2 diabetes mellitus (T2DM). However, increased adiposity alone does not explain the prevalence of T2DM, suggesting that additional factors contribute to the pathophysiology of T2DM. Studies conducted by our group during the previous project period suggest that levels of post-prandial circulating epinephrine (EPI) predict fasting glucose in the presence of central obesity. EPI binds to lipolytic ?-receptors increasing lipolysis i.e. hydrolysis of triglycerides into non-esterified fatty acids (NEFA). Our studies show that in the absence of high EPI levels, centrally obese individuals have normal fasting glucose levels, whereas centrally obese individuals with high EPI levels show impaired fasting glucose levels. We have also found that obese individuals who show an acute increase in plasma EPI levels to a glucose challenge have higher fasting NEFA levels, as well as higher endogenous glucose levels during the glucose challenge than obese individuals showing a decrease in EPI levels to the glucose challenge. Our work has thus led us to propose that the interaction of sympathoadrenal activity and central obesity plays an important role in the development of impaired glucose metabolism. Using a candidate gene approach and multiple studies available within the present PPG, we have showed that SNPs within the dopamine and beta-adrenergic receptor genes, as well as a SNP within the EBF1 gene are related to different aspects of our model including central adiposity, epinephrine levels, insulin sensitivity and glucose levels. The overall aim of this project is to test the effects of specific genotypes to parameters of the minimal model of glucose kinetics and visceral adiposity as well as to test G x E interactions to assess the moderating effect of chronic stress in order to further evaluate the mechanisms whereby sympathetic activity contributes to the development of impaired glucose metabolism in obese individuals. In addition, we plan to assess the interactive effect of EPI x visceral adiposity on minimal model outcomes and NEFA dynamics during the IVGTT.